AHR 基因-二恶英相互作用与塞韦索第二代健康研究中的出生体重。
AHR gene-dioxin interactions and birthweight in the Seveso Second Generation Health Study.
机构信息
Center for Environmental Research and Children's Health (CERCH), School of Public Health, University of California, Berkeley, CA, USA.
Department of Laboratory Medicine, University of Milan-Bicocca, Hospital of Desio, Desio-Milano, Italy.
出版信息
Int J Epidemiol. 2018 Dec 1;47(6):1992-2004. doi: 10.1093/ije/dyy165.
BACKGROUND
2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is proposed to interfere with fetal growth via altered activity of the aryl hydrocarbon receptor (protein: AHR; gene: AHR) pathway which regulates diverse biological and developmental processes including xenobiotic metabolism. Genetic variation in AHR is an important driver of susceptibility to low birthweight in children exposed to prenatal smoking, but less is known about these genetic interactions with TCDD, AHR's most potent xenobiotic ligand.
METHODS
The Seveso Women's Health Study (SWHS), initiated in 1996, is a cohort of 981 Italian women exposed to TCDD from an industrial explosion in July 1976. We measured TCDD concentrations in maternal serum collected close to the time of the accident. In 2008 and 2014, we followed up the SWHS cohort and collected data on birth outcomes of SWHS women with post-accident pregnancies. We genotyped 19 single nucleotide polymorphisms (SNPs) in AHR among the 574 SWHS mothers.
RESULTS
Among 901 singleton births, neither SNPs nor TCDD exposure alone were significantly associated with birthweight. However, we found six individual SNPs in AHR which adversely modified the association between maternal TCDD and birthweight, implicating gene-environment interaction. We saw an even stronger susceptibility to TCDD due to interaction when we examined the joint contribution of these SNPs in a risk allele score. These SNPs were all located in noncoding regions of AHR, particularly in proximity to the promoter.
CONCLUSIONS
This is the first study to demonstrate that genetic variation across the maternal AHR gene may shape fetal susceptibilities to TCDD exposure.
背景
2,3,7,8-四氯二苯并对二恶英（TCDD）被认为通过改变芳烃受体（蛋白：AHR；基因：AHR）途径的活性来干扰胎儿生长，该途径调节包括异生物质代谢在内的多种生物和发育过程。AHR 中的遗传变异是暴露于产前吸烟的儿童中低出生体重易感性的重要驱动因素，但对于这些遗传与 TCDD（AHR 最有效的异生物质配体）的相互作用知之甚少。
方法
1996 年启动的 Seveso 妇女健康研究（SWHS）是一项队列研究，其中包括 981 名意大利妇女，她们在 1976 年 7 月的一次工业爆炸中接触到 TCDD。我们测量了母体血清中接近事故发生时采集的 TCDD 浓度。在 2008 年和 2014 年，我们对 SWHS 队列进行了随访，并收集了 SWHS 妇女在事故后怀孕的出生结局数据。我们在 574 名 SWHS 母亲中对 AHR 的 19 个单核苷酸多态性（SNP）进行了基因分型。
结果
在 901 例单胎分娩中，SNP 或 TCDD 暴露本身与出生体重均无显著相关性。然而，我们发现 AHR 中的六个个体 SNP 不良地改变了母体 TCDD 与出生体重之间的关联，表明存在基因-环境相互作用。当我们在风险等位基因评分中检查这些 SNP 的联合贡献时，我们发现由于相互作用，对 TCDD 的敏感性甚至更强。这些 SNP 都位于 AHR 的非编码区域，特别是在启动子附近。
结论
这是第一项表明 AHR 基因的母体遗传变异可能影响胎儿对 TCDD 暴露的易感性的研究。
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